Entry inhibitors, also known as fusion inhibitors, are a class of antiretroviral drugs, used in combination therapy for the treatment of HIV infection. This class of drugs interferes with the binding, fusion and entry of an HIV virion to a human cell. By blocking this step in HIV's replication cycle, such agents slow the progression from HIV infection to AIDS.
There are several key proteins involved in the HIV entry process.
- CD4, a protein receptor found on the surface of helper T cells in the human immune system, also called CD4+ T cells
- gp120, a protein on HIV surface that binds to the CD4 receptor
- CCR5, a second receptor found on the surface of CD4+ cells and macrophages, called a chemokine co-receptor
- CXCR4, another chemokine co-receptor found on CD4+ cells
- gp41, a HIV protein, closely associated with gp120, that penetrates the cell membrane
Binding, fusion, entry sequence
HIV entry into a human cells requires the following steps in sequence:
- The binding of HIV surface protein gp120 to the CD4 receptor
- A conformational change in gp120, which both increases its affinity for a coreceptor and exposes gp41
- The binding of gp120 to a coreceptor either CCR5 or CXCR4
- The penetration of the cell membrane by gp41, which approximates the membrane of HIV and the T cell and promotes their fusion
- The entry of the viral core into the cell
Entry inhibitors work by interfering with one aspect of this process.
- Maraviroc (Celsentri) binds to CCR5, preventing an interaction with gp120. It is also referred to as a "chemokine receptor antagonist" or a "CCR5 inhibitor."
- Enfuvirtide (Fuzeon) binds to gp41 and interferes with its ability to approximate the two membranes. It is also referred to as a "fusion inhibitor."
Investigation / experimental agents
Other agents are under investigation for their ability to interact with the proteins involved in HIV entry and the possibility that they may serve as entry inhibitors.
- TNX-355, a monoclonal antibody that binds CD4 and inhibits the binding of gp120
- PRO 140, a monoclonal antibody that binds CCR5
- BMS-488043, a small molecule that interferes with the interaction of CD4 and gp120
- Plerixafor was being developed to interfere with interaction between HIV and CXCR4, but showed little useful antiviral activity in recent trials.
- Epigallocatechin gallate, a substance found in green tea, appears to interact with gp120 as do several other theaflavins.
- Vicriviroc, similar to maraviroc, is currently undergoing clinical trials for FDA approval.
- Aplaviroc, an agent similar to maraviroc and vicriroc. Clinical trials were halted in 2005 over concerns about the drug's safety.
- b12 is an antibody against HIV found in some long-term nonprogressors. It has been found to bind to gp120 at the exact region, or epitope, where gp120 binds to CD4. b12 seems to serve as a natural entry inhibitor in some individuals. It is hoped that further study of b12 may lead to an effective HIV vaccine.
- Griffithsin, a substance derived from algae, appears to have entry inhibitor properties.
- DCM205, is a small molecule based on L-chicoric acid, an integrase inhibitor. DCM205 has been reported to inactivate HIV-1 particles directly in vitro and is thought to act primarily as an entry inhibitor.
- CD4 specific Designed Ankyrin Repeat Proteins (DARPins) potently block viral entry of diverse strains and are being developed and studied as potential microbicide candidates 
- ^ Biswas P, Tambussi G, Lazzarin A (2007). "Access denied? The status of co-receptor inhibition to counter HIV entry" (abstract page). Expert Opin Pharmacother 8 (7): 923–33. doi:10.1517/146565220.127.116.113. PMID 17472538. http://www.expertopin.com/doi/abs/10.1517/14656518.104.22.1683.
- ^ Pugach P, Ketas TJ, Michael E, Moore JP (August 2008). "Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors". Virology 377 (2): 401–7. doi:10.1016/j.virol.2008.04.032. PMC 2528836. PMID 18519143. http://linkinghub.elsevier.com/retrieve/pii/S0042-6822(08)00272-9.
- ^ Emau P, Tian B, O'keefe BR, et al. (2007). "Griffithsin, a potent HIV entry inhibitor, is an excellent candidate for anti-HIV microbicide". J. Med. Primatol. 36 (4–5): 244–53. doi:10.1111/j.1600-0684.2007.00242.x. PMID 17669213. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0047-2565&date=2007&volume=36&issue=4-5&spage=244.
- ^ Duong YT, Meadows DC, Srivastava IK, Gervay-Hague J, North TW (May 2007). "Direct inactivation of human immunodeficiency virus type 1 by a novel small-molecule entry inhibitor, DCM205". Antimicrob. Agents Chemother. 51 (5): 1780–6. doi:10.1128/AAC.01001-06. PMC 1855571. PMID 17307982. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1855571.
- ^ Schweizer, A; Rusert, P, Berlinger, L, Ruprecht, CR, Mann, A, Corthésy, S, Turville, SG, Aravantinou, M, Fischer, M, Robbiani, M, Amstutz, P, Trkola, A (2008 Jul 25). "CD4-specific designed ankyrin repeat proteins are novel potent HIV entry inhibitors with unique characteristics.". PLoS pathogens 4 (7): e1000109. doi:10.1371/journal.ppat.1000109. PMC 2453315. PMID 18654624. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2453315.
Antiviral drugs: antiretroviral drugs used against HIV (primarily J05) Entry/fusion inhibitors
(Discovery & development)
inhibitors (RTIs)Non-Nucleoside (NNRTI)
(Discovery & development)
Integrase inhibitors Maturation inhibitors Protease Inhibitors (PI)
(Discovery and development)1st generation2nd generation
Combined formulations Experimental agentsTRIM5alpha (gene)Tat antagonistsTrichosanthinOtherAbzyme • Calanolide A • Ceragenin • Cyanovirin-N • Diarylpyrimidines • Epigallocatechin gallate (EGCG) • Foscarnet • Griffithsin • Hydroxycarbamide • Miltefosine • Portmanteau inhibitors • Seliciclib† • Synergistic enhancers • Tre recombinase • Zinc finger protein transcription factor • KP-1461† • Cobicistat†Failed agents #WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III °DHHS preferred first-line agent. ◊Formerly or rarely used agent.
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